TransCon IL-2 β/γ, a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog, demonstrates improved pharmacokinetics and profound expansion of cytotoxic immune cells in non-human primates.
Authors: David Rosen, Anne Månsson Kvarnhammar, Janne Damm Olling, Burkhardt Laufer, Thomas Knappe, Jens Jakob Karlsson, Thomas Kurpiers, Joachim Zettler, Josefine Runz, Frank Faltinger, Laura Viet, Mathias Krusch, Meike Schnabel, Diana Reich, Philipp Glock, Stina Mui Singel, Kennett Sprogøe, Kristin Laura Abel, Vibeke Miller Breinholt, Juha Punnonen
Journal: Journal of Clinical Oncology (2022)

2563 Background: Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe side effects including cytokine release syndrome (CRS) and vascular leak syndrome (VLS). This is believed to be due to activation of IL-2Rα + endothelial cells and inflammatory eosinophils as well as high C max due to the short half-life requiring frequent high dose administrations. Also, potent activation of immunosuppressive IL-2Rα + regulatory T cells (Tregs) may limit IL-2’s efficacy. TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog designed to optimally address these shortcomings. Methods: Naïve male and female cynomolgus monkeys received 2-3 doses of TransCon IL-2 β/γ intravenously Q2W. Blood samples were taken to assess plasma concentrations of IL-2 β/γ (active drug), serum cytokines, hematology and immunophenotyping. Histopathology was also performed. Results: Administration of TransCon IL-2 β/γ induced robust increases in absolute lymphocyte counts (ALC), with no/minor increases in eosinophil counts. The increase in ALC was primarily driven by potent activation and expansion of CD8 + T cells, NK cells and γδ T cells, relative to CD4 + T cells and Tregs. At doses with maximum pharmacodynamic (PD) responses, TransCon IL-2 β/γ induced on average &gt; 20-fold ALC increases, &gt; 19-fold CD8 + T cell increases, &gt; 50-fold Effector Memory CD8 + T cell increases, &gt; 18-fold NK cell increases and &gt; 400-fold γδ T cell increases compared to pre-dose levels. These changes corresponded with a low C max and a long effective half-life ( &gt; 30 hours) for IL-2 β/γ. A clear induction of soluble CD25 and chemokine MCP-1 was seen after dosing, while levels of IL-5, IL-6, IFN-γ and TNF-α remained low. Further, histopathology showed no signs of vascular damage, tissue necrosis, pulmonary edema or eosinophilia. Conclusions: In cynomolgus monkeys, TransCon IL-2 β/γ demonstrated remarkable PD responses in CD8 + T cells, NK cells and γδ T cells over Tregs and eosinophils. No signs of VLS or CRS were observed. These results are likely due to the selective IL-2Rβ/γ bias along with the slow and sustained release of IL-2 β/γ resulting in low C max and long circulatory half-life enabled by the TransCon prodrug technology. The massive expansion of γδ T cells, which are known to possess considerable anti-tumor activity, is to our knowledge a unique finding for TransCon IL-2 β/γ among IL-2 variants in clinical development. Altogether, the responses seen in monkeys are suggestive of a potentially substantial improvement in the therapeutic index beyond what has been achieved by aldesleukin or new IL-2 variants to date. TransCon IL-2 β/γ is currently being evaluated in a clinical Phase 1/2 trial as monotherapy and in combination with pembrolizumab (NCT05081609).